Many commonly employed cancer therapeutics tend to induce substantial toxicity due to their inability to selectively target proliferating tumor cells. Rather, these traditional chemotherapeutic agents act non-specifically and often damage or eliminate normally proliferating healthy tissue along with the tumor cells. Quite often this unintended cytotoxicity limits the dosage or regimen that the patient can endure, thereby effectively limiting the therapeutic index of the agent. As a result, numerous attempts have made to target cytotoxic therapeutic agents to the tumor site with varying degrees of success. One promising area of research has involved the use of antibodies to direct cytotoxic agents to the tumor so as to provide therapeutically effective localized drug concentrations.
In this regard it has long been recognized that the use of targeting monoclonal antibodies (“mAbs”) conjugated to selected cytotoxic agents provides for the delivery of relatively high levels of such cytotoxic payloads directly to the tumor site while reducing the exposure of normal tissue to the same. While the use of such antibody drug conjugates (“ADCs”) has been extensively explored in a laboratory or preclinical setting, their practical use in the clinic is much more limited. In certain cases these limitations were the result of combining weak or ineffective toxins with tumor targeting molecules that were not sufficiently selective or failed to effectively associate with the tumor. In other instances the molecular constructs proved to be unstable upon administration or were cleared from the bloodstream too quickly to accumulate at the tumor site in therapeutically significant concentrations. While such instability may be the result of linker selection or conjugation procedures, it may also be the result of overloading the targeting antibody with toxic payloads (i.e., the drug to antibody ratio or “DAR” is too high) thereby creating an unstable conjugate species in the drug preparation. In some instances construct instability, whether from design or from unstable DAR species, has resulted in unacceptable non-specific toxicity as the potent cytotoxic payload is prematurely leached from the drug conjugate and accumulates at the site of injection or in critical organs as the body attempts to clear the untargeted payload. As such, relatively few ADCs have been approved by the Federal Drug Administration to date though several such compounds are presently in clinical trials. Accordingly, there remains a need for stable, relatively homogeneous antibody drug conjugate preparations that exhibit a favorable therapeutic index.